The molecular mechanisms controlling the early development of the central nervous system in mammals remain poorly understood. Mouse genetics serves as a powerful tool to investigate the process. Here I will study a new recessive lethal mouse mutant, sister of open brain (sopb), exhibiting severe neural tube patterning defects. sopb was obtained from a phenotype-based genetic screen using N-ethyl-nitrosourea (ENU). Homozygous mutant embryos fail to close the cephalic and spinal neural tube, and exhibit other defects including supernumerary digits and poorly developed eyes. The neural tube of sopb mutants is ventralized with the ectopic expression of Shh target genes, and sopb appears to function downstream of Shh. The hypothesis of this project is that sopb acts as an antagonist of the Shh signaling pathway. This study will focus on four aims: 1) to investigate the primary defects in sopb mutants with respect to neural tube patterning based on the expression of various markers of cell type and of genes involved in cell-cell signaling, 2) to test whether the wild-type sopb gene product acts cell autonomously or non-cell autonomously for neural cell type specification using chimera analysis, 3) to place the sopb gene in the Shh signal transduction pathway using epistasis analysis, and 4) to positionally clone the sopb gene to understand its molecular function. The Sonic hedgehog (Shh) pathway plays important roles in embryonic patterning. The abnormal activity of the pathway has been shown to cause birth defects and various cancers. Therefore, identification and characterization of novel components of the pathway, such as sopb, will have important clinical implications.